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Abstract

Asthma in the mother is one of the most reproducible risk factors for asthma in her child, however the underlying mechanisms are unknown. In this thesis, I identified and characterized genetic and epigenetic mechanisms underlying maternal transmission of asthma risk. First, I examined ADAR-mediated miRNA editing in bronchial epithelial cells (BECs) from 142 asthma cases and controls. I identified A-to-I editing of a microRNA (miRNA), miR-200b-3p, that was significantly associated with moderate and severe, but not mild, asthma. I also found that the expression of the primary A-to-I editing gene, ADAR, was significantly decreased in asthma cases with an asthmatic mother. These results suggested that maternal asthma may alter the gene regulatory landscape in BECs at the ADAR locus in utero, with long-lasting effects on ADAR-mediated editing of miR-200b-3p and leading to more severe asthma in adulthood. Second, I identified genome-wide DNA methylation patterns in BECs from asthmatic children with an asthmatic mother that differed compared to asthmatic children without an asthmatic mother and to controls. Maternal asthma-associated DNA methylation signatures reflected different endotypes of asthma severity. Overall, I suggested that the maternal asthma in utero environment alters epigenetically-mediated developmental pathways in the lower airways that lead to subtypes of severe asthma in adulthood. Lastly, I tested for maternal asthma-associated mitochondrial DNA (mtDNA) variants and haplogroups in nine ethnically diverse cohorts. Associations between mtDNA variants and haplogroups with asthma were primarily in maternal asthma dyads and not in paternal asthma dyads. These results indicated that some of the risk for asthma in children of asthmatic mothers may be due to variation inherited from the maternally-inherited mtDNA genome.

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